Understanding how cardiac myocytes transduce stretch signaling to alter nuclear transcriptional events will contribute greatly to our knowledge of the hierarchical mechanism which directs cardiac hypertrophy triggered by hypertension or structural heart disease. We propose the hypothesis that the effects of activated RhoA on the actin cytoskeleton and integrin activation might be the key mediator that links stretch dependent signaling to cardiac nuclear transcription factor performance, thus inducing cardiac hypertrophy in vivo. RhoA, a small molecular weight GTP-binding proteins acts a molecular switch that controls various cell functions and has received attention at a potential mediator of hypertrophic signals. The overall objective is to decipher the signaling pathways that link the potential receptors of the mechanical stretch signal to cytoskeleton assembly. and to the cardiac growth response. Aim I: to determine if stretch induces cardiac hypertrophy via activation of the RhoA signaling pathway in isolated cardiac myocytes. Aim II: to determine if focal adhesion kinase integrates the stretch signal through tyrosine auto-phosphorylation and/or by association with downstream signaling factors in isolate cardiac myocytes. Aim III: to determine if stretch activates integrin-linked kinase and if expression of kinase deficient of kinase deficient integrin-linked kinase attenuates cardiac hypertrophy facilitated by pressure overload. Aim IV: to determine the role of RhoA, focal adhesion kinase and integrin linked kinase and their mutated dominant negative species and whether they modify cardiac hypertrophic responses facilitated by pressure overload in inducible transgenic mouse models.